Immodibenzyl compounds



United States ,IMINODIBENZYL COMPOUNDS Paul Gailliot, Paris, and JeanRobert, Gentilly, France,

assignors to Societe des Usines Chimiques Rhone- Poulenc, Paris, France,a French body corporate No Drawing. Application October 1, 1956,

Serial No. 612,966 1 Claims priority, application France October 26,1955 4 Claims. (Cl. 260-239) Gilt-CH2 t 10 11\ 1 2 \5/ 3 N wherein Arepresents the trivalent hydrocarbon group the various nitrogen groupsbeing attached to any of the three free valencies thereof and the groupsR are the same or diiferent and represent when taken separately ahydrogen atom or a lower alkyl group and when taken together with thenitrogen atom (i. e. as the group --N(R)2) represent a residue of aheterocyclic amine such as pyrrolidino, piperidino or morpholino,corresponding compounds in which one or both of the benzene nuclei of'the iminodibenzyl carry halogen, lower alkyl or lower alkoxysu-bstituent groups and the acid addition salts, the quaternary ammoniumderivatives and the addition compounds (in particular with8-chlorotheophyl1ine) of any .of the aforesaid compounds. By a loweralkyl or lower alkoxy group is meant a group containing not more than 4carbon atoms.

When the group A contains an asymmetric carbon atom the compounds mayexist both in the racemic form and the com-pounds in such Various forms.

The aforesaid new iminodibenzyl compounds are of tent:

value in. human therapy as gangl-ioplegics, local anaes-" as asubstituent on the imino nitrogen atom by methods known per setor theintroduction of such a substituent 2,811,520 Patented Oct. 29, 1957 2grouping on a nitrogen atom, particularly a heterocyclic nitrogen atom.Such methods include:

(1) Condensation of a halogeno diamine of the type Hal (R)aN N (R) orone of its salts (where A and R have the meanings assigned to themabove) with the appropriate iminodibenzyl.

(2) Condensation'of a compound H N(R)2 where R has the meaning set forthabove, with an iminodibenzyl derivative of general Formula II:

Z Zi

where one of the two symbols Z represents an acid residue sealed tube,particularly when the compound HN(-R)2 is a volatile amine.

.(3) Heating, to effect decarboxylation, a compound of the generalFormula III:

' CHrCHz (R)zN III where A and R have the meanings assigned to themabove. (4) To produce compounds of general Formula I where the R groupsare lower alkyl groups, alkylation of the corresponding compounds ofFormula I where at least one of the R groups is replaced by a hydrogenatom, using methods of alkylation of amines known per se.

(5) Reduction of corresponding amides such as, for example the compoundsof the general Formulae IV, V and VI:

CH2-CH2 oma).

GONCR):

where R represents a hydrogen atom or an alkyl group containing not morethan 3 carbon atoms, and R and A have the meanings assigned to themabove.

(6) Reduction in the presence of a compound HN( R)2 of a derivative ofthe general Formulae VII or VIII:

ens-on, @t it) where R has the meaning assigned to it above, Arepresents a grouping and T represents a- -CHO or CN group. When T is a--ON group, the reaction may be carried out in the absence of thecompound HN(R)2 to give directly the corresponding primary amine.

(7) Cyclisation, preferably in a solvent selected from the class ofsubstituted amides of' lower aliphatic acids such as formarnides oracetamides, in the presence of a condensing agent (e. g. alkali metalhydroxide or carbonate) and if desired in the presence of a catalystsuch as copper powder, of a derivative of the general Formula IX:

N H Hal.

where A and R have the meanings assigned to them above and Hal is ahalogen atom.

Method 1 is the most advantageous. This reaction may be carried out inthe presence or absence of a solvent and in the presence or absence of acondensing agent. It is however convenient to use an aromatichydrocarbon solvent for example toluene or xylene, in the presence of acondensing agent, preferably selected from alkali metals and theirderivatives (such as, for example, hydrides, amides, hydroxides,alcoholates, metal alkyls or aryls) and more particularly metallicsodium, sodamide, powdered sodium or potassium, lithium hydride, sodiumtertbutylate, .butyllithium, and phenyllithium. The reaction ispreferably carried out at the boiling temperature of the solvent.

It is advantageous to use the halogeno-diamine in the form of the freebasein solution in, for example, benzene, toluene or xylene and to addit to the mixture of the other reactants in which the iminodibenzyl mayalready be present, at least in part, in the form of an alkali metalsalt. The reaction may also be carried out using a salt of thehalogeno-diamine but in this case a larger proportion of the condensingagent is preferably used in order to neutralise the acid of the saltemployed.

Isomerization may take place during the condensation and there is thenobtained a mixture of varying proportions of the two isomers of FormulaeX and XI:

OHrCHz N (iHg-ClT-CHzNCR):

These isomers may be separated, for example by crystallisation of a saltsuch as the dihydrochloride in alcohol, or by chromatography. It is not,however, essential to carry out this separation, since the two isomersgenerally have very similar pharmacodynamic properties.

The following examples in which the melting points indicated aredetermined on the Kofler bench, will serve to illustrate the inventionbut are not to be regarded as limiting it in any way:

Example I A mixture: of imi-nodibenzyl (6.65 g.), toluene (35 cc.) andsodamide (1.52 g.) is heated under reflux for 1 hour under nitrogen andan 11.5% solution'(53 cc.) of 1:3- vbis-dimethylamino-Z-chloropropane intoluene is then added over 1 hour. A-fter being heated for 10 hours.under reflux, the mixture is cooled and washed with water cc.) Thetoluene solution is extracted with normal hydrochloric acid (70, 30, 20and 20 cc. successively) and the combined aqueous acid solutions arewashed with ether (25 cc.) and then treated with aqueous sodiumhydroxide (d -l.33; 16 cc.). They are then extracted with ether (3X50cc.) and the combined ethereal extracts are, washed with water (30 cc.)and dried over sodium sulphate. The ether is removed on the water-bathand the residue is distilled in vacuo to give a mixture (6.14 g.) of 5-(2:3-bisdimethylamino- 1-propyl)iminodibenzyl and5-;(1:3-bis-dimethylamino-2- propyl )iminodibenzyl. On dissolving thismixture in isopropanol and treating with ethanolic hydrogen chloride,there is obtained 5-(2:3*bis-dimethylamino-l-propyl)- iminodibenzylhydrochloride, M. P. about 230-232 C.

By the action of methyl iodide on a solution in acetone of the basecorresponding to this hydrochloride, the corresponding monoiodoniethylate is obtained, M. P. 182- 184" C. By following theprocedure of this example but employing1:3-bis-diethylamino-2-chloropropane there is obtained a mixture of5-(2:3-bis-diethylamino-lpropyl)-iminodibenzyl and5-(l'z3-bis-diethylamino-2- propyl)imin odibenzyl, the former isomerbeing in preponderantamount and have B. P. 0.11 164-l'68 C.

Example H l:3-bis-dimethylamino 2 propyl-iminodibenzyl-S-carboxylate(3.4 g.), M. P. 72 C., is heated gradually from 185 to 250 C. untilevolution of carbon dioxide has ceased, which takes about an hour.. Theoily product obtained is dissolved in diethylether and the etherealsolution extracted with dilute hydrochloric acid. The solution is thenmade alkaline with dilute caustic soda, extracted with cliethyl etherand the ether removed from the extract to yield the product (base) as anoil (1.17 g.) having the correct acidimetric titre. By addition ofethereal hydrogen chloride to an acetone solution of this base there isobtained 54(2z3-bis-dimethylamino-lpropyl)iminodibenzyl dihydroclrloride, P. 227- 229 C.

The 1:3-bis-dimethyla-mino-Z-propyl-iminodibenzyl-S- carboxylate used asstarting material, of which the picrate has M. P. 174-175 0., can beprepared by condensing l:3abis-dimethylamino-Q-propanol withiminodibenzyl-S- carboxylic acid chloride, M. P. 120-121" C., itselfprepared by the action of phosgene on iminodibenzyl.

We claim:

1. A compound selected from the class consisting of iminodibenzylcompounds of the general formula: I

CHr-CH', 10 11 wherein A represents the trivalent hydrocarbon groupCHz-CHCH2'- the various nitrogen atoms being attached to any of thethree free valencies thereof, and the groups R are lower alkyl groupsand the acid addition salts, quaternary ammonium derivatives andaddition compounds of any of the said compounds where the additionalgroups are pharmaceutically acceptable.

2, 5 2: 3-bis-dimethylamino-l-propyl) iminodibenzyl.

3. 5'( 1 3-bis-dimethy1amino-2-propyl)imincdibenzyl.

4. 5 (2:3 bis-diethylamino-l-propyl)iminodibenzyl.

References Cited in the file of this patent UNITED STATES PATENTS

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF IMINODIBENZYLCOMPOUNDS OF THE GENERAL FORMULA: